Treatment of diseases caused by abnormal action of elastase

ABSTRACT

Compounds presented by the general formula: ##STR1## wherein Y is oxygen, R 2  is H, alkyl, alkoxy, alkoxymethyl, --COOR 3 , --CH 2  COOR 3 , --CH═CH--COOR 3 , halogen, --CF 3 , --COR 4 , --OCOR 4 , --CH 2  OCOR 4 , --SO 2  R 4 , --OSO 2  R 4 , --CONR 5  R 6 , --OCONR 5  R 6 , --SO 2  NR 5  R 6 , --COHN-- SO 2  NR 5  R 6 , --NHSO 2  R 7 , --NO 2 , --OH, --CH 2  OH, guanidino, benzyloxy, guanidinophenylthiomethyl, morpholinosulfonylphenoxymethyl, pyridyloxymethyl, or (1,1-dioxothiazol-3-yl)carbonyl, or when Y is sulfur, R 2  is H, alkyl, alkoxy, halogen, --COOR 3 , --CH 2  COOR 3 , --NO 2 , or --SO 2  NR 5  R 6 , and n represents an integer of one to five, and when n represents more than two, each or R 2  may be the same group or the different group and acid addition salts thereof have inhibitory effect on elastase, and, therefore, are useful for the treatment and/or prevention of diseases induced by abnormal enhancing of degradation of proteins such as elastin and the like, by the action of elastase in mammals, especially in human beings.

This is a division of application Ser. No. 06/929,317, filed 11/12/86now U.S. Pat. No. 4,843,094.

FIELD OF THE INVENTION

The present invention relates to derivatives of p-guanidinobenzoic acidand the pharmaceutical agents containing them as active ingredients.

More particularly, it relates to new derivatives of p-guanidinobenzoicacid of the general formula: ##STR2## (wherein all symbols are the samemeaning as described hereinafter.), and relates to elastase inhibitorscontaining, as active ingredient, derivatives of p-guanidinobenzoic acidof the general formula: ##STR3## (wherein all symbols are the samemeaning as described hereinafter).

BACKGROUND OF THE INVENTION

Lysosomal hydrolases of neutrophils have an important role for anorganism defense reaction against tissue damage caused by microbe orinflammation etc.

Elastase and cathepsin G, which belong to neutral serine proteinaselocally existed in azurophil granule mainly play a part in decompositionof a connective tissue.

Especially, elastase degrades elastic connective tissue by cleaving thecross-linking of elastin which directly maintains the elasticity of lungtissue etc., and by cleaving hydrophobic part of protein J. Cell. Biol.,40, 366 (1969) and degrades the cross-linking area of collagenselectively J. Biochem., 84, 559 (1978), and it acts on such asproteoglycans etc. J. Clin. Invest., 57, 615 (1976).

Elastase is inactivated by α₁ -proteinase inhibitor (α₁ -PI) that isnatural occurring inhibitor for serine, proteinase in vivo and theunbalance of enzyme and inhibitor system causes the destruction of thetissue [Schweiz. Med. Wshr., 114. 895 (1984)].

The turnover of elastin in normal tissue is very slow [Endocrinology,120, 92 (1978)], but the pathological acceleration in degradation ofelastin is found under various unsound state such as pulmonary emphysema[Am. Rev. Respir. Dis., 110, 254 (1974)], atherosclerosis [Lab. Invest.,22, 228 (1970)] and rheumatoid arthritis in [Neutral Proteases of HumanPolymorphonuclear Leukocytes, Urban and Schwarzenberg, Baltimore--Munich(1978), page 390], suggesting the relationship of elastase and diseases[Infection.Inflammation.Immunity, 13, 13 (1983)].

PRIOR ARTS

Under the background as mentioned above, recently the studies anddevelopment on elastase inhibitors have been conducted heartily, varioussubstances inhibiting elastase have been proposed and many patentapplications have been filed. However, elastase inhibitors consisting ofderivatives of guanidinobenzoic acid, as shown in the present invention,have not been known at all till now.

On the other hand, heretofore the various esters of p-guanidinobenzoicacid have been known. For example, when Y is an oxygen atom in thegeneral formulae (IA) and (IB)

(1) in the specification of Japanese Patent Kokoku No. 54-40534, thecompounds of the general formula: ##STR4## has been disclosed,

(2) in the specification of Japanese Patent Kokai No. 50-4038, thecompounds of the general formula: ##STR5## (wherein R^(a) represents anaromatic group, and an said aromatic group may be substituted by a loweralkyl group, a lower alkoxycarbonyl group, a carboxyl group, a carboxylower alkyl group, a carboethoxy lower alkyl group, a lower alkoxygroup, an acylamido group or a carbamoyl group)

(abstracted related points) have been disclosed,

(3) in the specification of Japanese Patent Kokoku No. 57-35870, thecompounds of the general formula: ##STR6## (wherein Z^(a) represents thegroup selected from the group consist of a carbon- carbon covalent bond,a methylene group, an ethylene group and a vinylene group) have beendisclosed,

(4) in the specification of Japanese Patent Kokai No. 55-55154, thecompounds of the general formula: ##STR7## (wherein Z^(b) represents amethylene group, an ethylene group or a vinylene group, and R^(b)represents a lower alkyl group.) have been disclosed,

(5) in the specification of Germany Patent Publication No. 3005580, thecompounds represented by the general formula: ##STR8## (wherein Z^(c)represents a sulfonyl group or the group represented by Z^(d) --CO,Z^(d) represents a bond, methylene, ethylene or vinylene, R^(c) and/orR^(d) represent a hydrogen atom or a alkyl group.) have been disclosed,

(6) in the specification of Germany Patent Publication No. 1905813, thecompounds of the general formula: ##STR9## (wherein R^(e) and/or R^(f)represent a hydrogen atom; an alkyl group, an aryl group, a nitro group,an amino group, an alkylamino group, a dialkylamino group, an alkoxygroup, a carboxy group, a carboalkoxy group or a halogen atom, 1represents an integer of zero or one.) have been disclosed.

(7) in the specification of U.S. Pat. No. 4,423,069, the method toinhibit conception by giving the compounds represented by the generalformula: ##STR10## [wherein Rg represents a halogen, a trihalomethyl, anitryl group, a formyl group, OR^(i), COR^(i), COOR^(i), CONH₂ orCONR^(j) R^(k) (wherein R^(i), R^(j) or R^(k) represent an alkyl groupof one to eight carbon atoms), R^(h) represents a hydrogen atom or thegroup represented by the symbol Rg.]and a salt thereof have beendisclosed,

(8) In the specification of Japanese Patent Kokai No. 61-43151, thecompounds represented by the general formula: ##STR11## (wherein R¹represents a hydrogen, a nitrile group or an ether group, R^(m)represents a hydrogen, an ether group, an ester group or a carbamoylgroup, except that R^(l) and R^(m) represent a hydrogen at the sametime.) and agents of depressing acrocine have been disclosed, On theother hand, when Y is a sulfur atom,

(9) In the specification of Japanese Patent Kokoku No. 55-42076, thecompounds described by the general formula: ##STR12## (wherein R^(n)represents a hydrogen atom or an ethoxycarbonyl group and symbol m'represents an integer of four to six) have been disclosed,

(10) in the specification of Japanese Patent Kokoku No. 56-3345, thecompounds described by the general formula: ##STR13## (wherein Arepresents a straight- or branched-chain alkylene group of one to tencarbon atoms, B represents p-phenylene group or divalent alicyclicgroup, symbol a represents zero or one, symbol b represents zero or one,the total number of a and b represent one or two, R^(o) represents thegroup selected from the group of an ethoxycarbonylalkyl group of one toten carbon atoms, the alicyclic group, a phenyl group, a naphtyl groupand a phenylalkyl group and the alicyclic group and the aromatic groupdescribed above, may be replaced by a lower alkyl group, anethoxycarbonyl group, an ethoxycarbonyl-lower alkyl group, acarboxyalkyl group, a halogen atom, an alkoxy group, an acylamino group,an alkylsulfonyl group, a carboxy group, a thiocarboxy group, amercaptocarbonyl group, a nitro group or a carbamoyl group.) have beendisclosed.

In the specifications (1) to (6), (9) and (10) mentioned above, it isdescribed that all these compounds have inhibitory effects on trypsinand plasmin, and therefore, are useful for the treatment of acutepancreatitis and bleeding diseases as anti-plasmin agents. And there isno description about an inhibitory effect of these compounds on elastasein the above specifications, nor report concerning about the examinationof the effect so far.

Likewise, in the specifications (7) and (8) mentioned above, it isdescribed that all compounds have inhibitory effects on acrocine etc.which are important enzymes in fertilization, and accordingly it isuseful as the method for inhibition of conception and as an agent forinhibition of fertilization.

Elastase belongs to serine proteinase like trypsin and plasmin(hereinafter described "trypsin and plasmin" as "other serineproteinase" in order to distinguish from elastase), but is muchdifferent from them in point of enzymatic property and substratespecificity. Accordingly, it is reasonable to consider that elastase isa quite different enzyme group from other serine proteinase essentially,and therefore, the development of elastase inhibitors should beconsidered from a quite different point of view.

That is, elastase, especially human neutrophil elastase is a basicglycoprotein ["Protein Degradation in Health and Disease", edited by D.Evered and J. Whelan, page 51, Excerpta Medica, Amsterdam (1980)] havingthe molecular weight of about 30,000 Biochem. J., 155, 255 (1976), itsisoelectric point being between pH 8.77 and 9.15 [Anal. Biochem., 90,481 (1978)], and therefore, it is different from other serineproteinases in proteinic property.

Furthermore, in substrate specificity, elastase is classified asendopeptidases which mainly cleave a protein at the carboxy terminal ofalanine residue. Even in this point, elastase is different from otherserine proteinase. As said above, there is the fundamental differencesbetween both enzyme, and therefore it is entirely impossible toanalogize elastase inhibitors from other serine proteinase inhibitors.

PURPOSE OF THE INVENTION

As the result of energestic investigations in order to find new elastaseinhibitory agents that have quite different chemical structure fromconventional one, based on these findings, the present inventors havenow found the fact that a kind of derivatives of p-guanidinobenzoic acidphenyl ester, known as inhibitory agents of other serine proteinase,unexpectedly has an inhibitory effect on elastase, then completed thisinvention.

The fact that inhibitory agents of other serine proteinase have aninhibitory effect on elastase, has been confirmed experimentally for thefirst time, and was never anticipated until now.

CONSTITUTION OF THE INVENTION

Accordingly, the present invention relates to the novel compounds, i.e.derivatives of p-guanidinobenzoic acid of the general formula: ##STR14##[wherein Y represents an oxygen atom or a sulfur atom and (i) when Y isan oxygen atom, (R¹)m represents the group selected from 2-methyl,3-methyl, 2,3-dimethyl, 3,5-dimethyl, 3-ethyl, 2-methoxy, 3-methoxy,4-methoxy, 3,5-dimethoxy, 5-etanesulfonyloxy-3-methoxymethyl,3-hydroxy-5-methoxymethyl, 5-(4-guanidinobenzoyloxy)-3-methoxymethyl,3-carboxy-2-chloro, 3,5-dicarboxy, 2-carboxy-5-chloro,2-chloro-3-methoxycarbonyl, 2-chloro-4-methoxycarbonyl,3-chloro-4-methoxycarbonyl, 5-chloro-2-methoxycarbonyl,3-chloro-5-methoxycarbonyl, 3,5-bis(isopropoxycarbonyl), 5-chloro-2-isopropoxycarbonyl, 2-chloro-3-isopropoxycarbonyl,3-sec-butoxycarbonyl-2-chloro, 3-methoxycarbonylmethyl,2-chloro-3-methoxycarbonylmethyl, 2-chloro-4-methoxycarbonylmethyl,3-chloro-4-methoxycarbonylmethyl, 4-(2-methoxycarbonylvinyl), 2-fluoro,3-fluoro, 4-fluoro, 2,6-difluoro, 2,3-difluoro, 2,3,4,5,6-pentafluoro,2-chloro, 3-chloro, 4-chloro, 2,5-dichloro, 2,6-dichloro, 3,5-dichloro,3-chloro-5-methoxy, 4-chloro-3-methoxy, 2-chloro-5-methoxy, 2-bromo,3-bromo, 4-iodo, 2-trifluoromethyl, 3-trifluoromethyl,3,5-bistrifluoromethyl, 3-acetyl, 2-acetyl-5-methoxy,2-acetyl-5-propoxy, 2-acetyl-5-chloro, 5-chloro-2-propionyl,5-chloro-2-isobutyryl, 3-benzoyl, 4-benzoyl, 4-benzoyl-2-chloro,4-benzoyl-2,3-dichloro, 5-chloro-2-cyclopentylacetyl, 3-acetoxy,4-acetoxy, 5-acetoxy-3-chloro, 3-chloro-5-propionyloxy, 3-benzoyloxy,3-(4-guanidinobenzoyloxy), 3,5-bis(4-guanidinobenzoyloxy),3-acetyl-5-(4-guanidinobenzoyloxy),5-(4-guanidinobenzoyloxy)-3-methoxycarbonyl, 3-chloro-5-(4-guanidinobenzoyloxy), 5-(4-guanidinobenzoyloxy)-3-methoxy,5-(4-guanidinobenzoyloxy)-3-methyl, 5-acetoxymethyl-3-chloro, 4-mesyl,5-mesyloxy-3-methoxy, 3-chloro-5-mesyloxy, 3-chloro-5-ethanesulfonyloxy,3-chloro-5-isopropanesulfonyloxy, 5-benzenesulfonyloxy-3-chloro,5-ethanesulfonyloxy-3-methyl, 5-carbamoyl-3-chloro,3-(N,N-dimethylcarbamoyl), 2-chloro-3-(N-methylcarbamoyl),3-(4-guanidinobenzoyloxy)-5-(N-methylcarbamoyl),3,5-bis(N-ethylcarbamoyl), 3,5-bis(N-propylcarbamoyl),5-(N-benzylcarbamoyl)-3-(4-guanidinobenzoyloxy),3-chloro-5-{N-(3-pyridyl)carbamoyl},3-chloro-5-(N,N-dimethylcarbamoyloxy), 3-chloro-5-(N-ethylcarbamoyloxy),3-sulfamoyl, 3-chloro-4-(N,N-dimethylsulfamoyl),2-(N,N-diethylsulfamoyl), 3-(N,N-diethylsulfamoyl),4-(N,N-diethylsulfamoyl), 3-chloro-4-(N,N-diethylsulfamoyl),3-chloro-5-(N,N-diethylsulfamoyl), 4-(N,N-diethylsulfamoyl)-2-fluoro,4-(N,N-dipropylsulfamoyl), 4-(1-pyrrolidinylsulfonyl),3-piperidinosulfonyl, 3-morpholinosulfonyl, 4-morpholinosulfonyl,3-chloro-5-{N-(4-sulfamoylphenyl)carbamoyl},3-chloro-5-[N-{4-(N,N-dimethylsulfamoyl)phenyl}carbamoyl],3-chloro-5-[N-{4-(N,N-diethylsulfamoyl)phenyl}carbamoyl],2-chloro-5-(N-mesylamino), 3-chloro-5-(N-ethanesulfonylamino), 3-nitro,4-nitro, 3-hydroxy-5-methyl, 5-hydroxy-3-methoxy,5-hydroxy-3-methoxycarbonyl,3chloro-5-hydroxy-3-(4-guanidinobenzoyloxy)-5-hydroxy,5-hydroxy-3-(N-methylcarbamoyl), 3-(N-benzylcarbamoyl)-5-hydroxy,3-chloro-5-hydroxymethyl, 3-guanidino, 4-guanidino, 2-chloro-5-guanidino, 5-benzyloxy-3-chloro,3-chloro-5-(4-guanidinophenylthiomethyl),-chloro-5-(4-morpholinosulfonyl)phenoxymethyl,3-methoxy-5-(4-morpholinosulfonyl)phenoxymethyl,3-chloro-5-(3-pyridyl)oxymethyl,3-methoxy-5-(1,1-dioxothiazol-3-yl)carbonyl and3-chloro-5-(1,1-dioxothiazol-3-yl)carbonyl group.

(ii) when Y is a sulfur atom, (R¹)m represents the group selected from2-methyl, 3-methyl, 4-methyl, 2-methoxy, 3-methoxy, 4-methoxy, 4-fluoro,2-chloro, 3-chloro, 4-chloro, 2,5-dichloro, 2,6-dichloro, 3,4-dichloro,2-bromo, 2-methoxycarbonyl, 4-carboxy, 4-carboxymethyl,4-ethoxycarbonylmethyl, 4-nitro and 4-(N,N-diethylaminosulfonyl)group.or an acid addition salt thereof.

In the group of compounds described in the general formula (IA), thereare some compounds contained in each invention described in the aboveitem Prior art as the broad scope, but there is no specific descriptionabout individual compound. Accordingly, all compounds represented by thegeneral formula (IA) are considered to be quite novel.

Further, the present invention relates to the novel use as elastaseinhibitors containing derivatives of p-guanidinobenzoic acid, as activeingredient, represented by the general formula: ##STR15## [wherein Yrepresents an oxygen atom or a sulfur atom and (i) when Y is an oxygenatom, R² represents

(i) a hydrogen atom,

(ii) an alkyl group of one to four carbon atoms,

(iii) an alkoxy group of one to four carbon atoms,

(iv) an alkoxymethyl group of two to five carbon atoms,

(v) group represented by the formula: COOR³ (wherein R³ represents ahydrogen atom or an alkyl group of one to four carbon atoms.),

(vi) a group represented by the formula: CH₂ COOR³ (wherein R³ is thesame meaning as described hereinbefore.),

(vii) a group represented by the general formula: CH₂ CHCOOR³ (whereinR³ is the same meaning as described hereinbefore.),

(viii) a halogen atom,

(ix) a trifluoromethyl group,

(x) a group represented by the formula: COR⁴ (wherein R⁴ represents analkyl group of one to four carbon atoms, a phenyl group, guanidinophenylgroup, cyclopentylmethyl group or cyclohexylmethyl group.),

(xi) a group represented by the formula: OCOR⁴ (wherein R⁴ is the samemeaning as described hereinbefore.),

(xii) a group represented by the general formula: CH₂ OCOR⁴ (wherein R⁴is the same meaning as described hereinbefore.),

(xiii) a group represented by the general formula: SO₂ R⁴ (wherein R⁴ isthe same meaning as described hereinbefore.),

(xiv) a group represented by the general formula: OSO₂ R⁴ (wherein R⁴ isthe same meaning as described hereinbefore.),

(xv) a group represented by the general formula: CONR⁵ R⁶ (wherein R⁵and R⁶ represent a hydrogen atom, an alkyl group of from one to fourcarbon atoms, a phenyl group, a benzyl group, a pyridyl groupindependently, or R⁵, R⁶ and a nitrogen atom, to which R⁵ and R⁶ arelinked, together represent a pyrrolidinyl group, a piperidino group ormorpholino group.),

(xvi) a group represented by the general formula: OCONR⁵ R⁶ (wherein R⁵and R⁶ are the same meaning as described hereinbefore.),

(xvii) a group represented by the general formula: SO₂ NR⁵ R⁶ (whereinR⁵ and R⁶ are the same meaning as described hereinbefore.),

(xviii) a group represented by the general formula: ##STR16## (whereinR⁵ and R⁶ are the same meaning as described hereinbefore.),

(xix) a group represented by the general formula: NHSO₂ R⁷ (wherein R⁷represents an alkyl group of from one to four carbon atoms or a phenylgroup.),

(xx) a nitro group,

(xxi) a hydroxy group,

(xxii) a hydroxymethyl group,

(xxiii) a guanidino group,

(xxiv) a benzyloxy group,

(xxv) a guanidinophenylthiomethyl group,

(xxvi) a morpholinosulfonylphenoxymethyl,

(xxvii) a pyridyloxymethyl or

(xxviii) (1,1-dioxothiazol-3-yl)carbonyl group.

(ii) when Y is a sulfur atom, R² represents

(i) a hydrogen atom,

(ii) an alkyl group of one to four carbon atoms,

(iii) an alkoxy group of one to four carbon atoms,

(iv) a halogen atom,

(v) a group represented by the formula: COOR³ (wherein R³ is the samemeaning as described hereinbefore.),

(vi) a group represented by the formula: CH₂ COOR³ (wherein R³ is thesame meaning as described hereinbefore.),

(vii) a nitro group or

(viii) a group represented by the formula: SO₂ NR⁵ R⁶ (wherein R⁵ and R⁶are the same meaning as described hereinbefore.)

and symbol n represents an integer of one to five, and when symbol nrepresents two or more, each of R² may be the same group or thedifferent group.] or an acid addition salt thereof.

In this specification containing claims, the term "an alkyl group" meansthe straight- or branched-chained alkyl group. In the general formula(IB), as the alkyl group represented by R², as the alkyl moiety in thealkoxy group represented by R² and as the alkyl group represented by R³,R⁴, R⁵, R⁶ and R⁷, a methyl, an ethyl, a propyl, a butyl group and theisomer thereof are cited, and all of them are preferred.

In the general formula (IB), as the halogen atom represented by R², afluorine atom, a chlorine atom, a bromine atom and an iodine atom arecited, and all of them are preferred.

In the general formula (IB), as the group represented by R², and allgroup represented by (i) to (xxvii) is preferred.

The acid addition salts of the compounds represented by the generalformula (IA) and (IB) are preferably non-toxic and water-soluble.

Suitable acid addition salts include, for example, an inorganic acidaddition salt such as hydrochloride, hydrobromide, hydroiodide, sulfate,phosphate, nitrate, or an organic acid addition salt such as acetate,lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate,benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate.

All compounds of the present invention, represented by the generalformula (IB) [including the compounds represented by the general formula(IA)] may be prepared by well-known methods.

For example, it may be prepared by reacting an acid addition salt of acompounds represented by the general formula: ##STR17## (wherein Xrepresents an halogen atom) with a compounds represented by the generalformula: ##STR18## (wherein Y, R² and n are the same meaning asdescribed hereinbefore).

As the above reaction is the condensation accompanied by the formationof hydrogen halide, it is advantageous to use a dehydrohalogenationagent to promote the reaction.

As for the dehydrohalogenation agent, there can be used a tertiaryorganic amine, or if desired, there can be used a inorganic base such asa metal bicarbonate, etc.

As a tertiary organic amine, there can be used aliphatic, aromatic orheterocyclic amine, for example, triethylamine, tributylamine,dimethylaniline, pyridine and the like.

Particularly, pyridine is preferable because it is useful also as asolvent of reaction ingredient.

Further, as an inorganic base, there can be used, for example, sodiumbicarbonate, sodium carbonate, sodium hydroxide and the like.

As a solvent there can be used, for example, benzene, toluene,tetrahydrofuran, pyridine and the like, and as described above, pyridineacts also as a dehydrohalogenation agent and is, therefore, particularlypreferable.

Since the reaction proceeds comparatively fast, it may be carried out atthe room temperature, or if desired, with a little cooling, generallythe reaction may be carried out at a temperature from 0° C. to the roomtemperature.

The reaction time varies depending upon the reaction temperature to beused, and it is generally 30 minutes to 4 hours, preferably 30 minutesto 2.5 hours.

In carrying out the reaction, the starting material (III) describedabove is dissolved in a solvent, preferably in pyridine, the startingmaterials (II) is added into above solution.

When pyridine is used as a solvent, the compound (II) is not dissolvedtherein and therefore the reaction is hetetogeneous system. However thedesired product is soluble in pyridine, and therefore the reactionmixture becomes homogeneous with the progress of the reaction. In thecase where any other solvent than pyridine is used, the reaction mixtureis not always homogeneous but the reaction can be carried out in aheterogeneous system.

The desired product is obtained as a salt with hydrogen halide. Theproduct may be separated and purified by the following post-treatment.That is to say, the reaction mixture is concentrated or not concentrateddepending upon the used solvent. If not concentrated, the product iscrystallized as the carbonate salt by adding sodium bicarbonate to thereaction mixture. Particularly when pyridine is used as a solvent, thecarbonate salt of the product is outlined as crystals by treating thereaction product mixture with sodium bicarbonate, without evaporationand concentration. Of course, it is possible to obtain the product bythe evaporation of the solvent, but it is preferable that the product iscrystallized as a salt as mentioned above, because in the latter casethe product is higher in purity than in the former treatment.

The compounds (IB) of the present invention thus obtained can beconverted further, if desired, to a suitable acid addition saltdescribed above by known methods.

Besides, in the case that the product is crystallized as no salt in theroute of conversion to a salt mentioned above, the product can bepurified by column chromatography using silica-gel, etc.

The starting materials (II), used in the above-mentioned reaction, canbe prepared by the conventional method that p-guanidinobenzoic acid maybe reacted with thionylchloride.

In this case, the starting materials (II) can be prepared as the saltwith hydrogen halide, especially hydrochloride.

The starting materials (II) may be obtained as the salt with a hydrogenhalide which is by-produced in the formation of acid halide (II) fromguanidinobenzoic acid, and it is advantageous that the obtained salt maybe used without any operation.

The compounds represented by the general formula (III) are knowncompounds, or can be preparated easily by the known methods.

Further, of the compound of the present invention represented by thegeneral formula (IB), the compound wherein at least one group of R²represent a carboxyl group, that is, the compounds represented by thegeneral formula: ##STR19## (wherein R^(2a) represents the groupshereinbefore described for R² except for a carboxy group, and prepresents an integer of between one to five and q represents zero andan integer of between one to four, and the total number of p and qrepresented an integer of between one to five.) can be obtained bysubjecting the compounds represented by the general formula: ##STR20##(wherein symbol φ represents a phenyl group and the other symbols arethe same meaning as described hereinbefore) to the reaction foreliminating benzyl group. The said reaction for eliminating benzyl groupmay be carried out, for example, using anhydrous solution of hydrogenbromide-acetic acid in an atmosphere of an inert gas (e.g. argon,nitrogen etc.).

It is suitable that the reacticn temperature is generally at 0° to 50°C., preferably at the room temperature.

And the compound (IV) can be obtained by subjecting the acid additionsalt of the compounds represented by the general formula (II) and thecompounds represented by the general formula: ##STR21## (wherein allsymbols are the same meaning as described hereinbefore.) toesterification reaction.

This reaction may be carried out by the same conditions as mentionedhereinbefore.

And the compound (V) can be obtained by subjecting the compoundsrepresented by the general formula: ##STR22## (wherein all symbols arethe same meaning as described hereinbefore.) to benzylation reaction.

The benzylation reaction may be carried out by the known methods.

The compound represented by the general formula (VI) is the knowncompound or can be easily prepared by the known methods.

In the compound of present invention represented by the general formula(IB), the compound wherein at least one group of R² represents ahydroxymethyl group, i.e., the compound represented by the generalformula: ##STR23## (wherein R^(2b) represents the groups hereinbeforedescribed for R² except for a hydroxymethyl group, and r represents aninteger of between one to five and s represents zero and an integer ofbetween one to four, and the total number of r and s represented aninteger of between one to five, the other symbols are the same meaningas described hereinbefore.) can be obtained by subjecting the compoundsrepresented by the general formula: ##STR24## (wherein THP represents2-tetrahydropyranyl group and the other symbols are the same meaning asdescribed hereinbefore.) to reaction for eliminating a THP group.

The said reaction for eliminating a THP group may be carried in anaqueous solution of an organic acid such as acetic acid, propionic acid,oxalic acid, p-toluenesulfonic acid (preferably, acetic acid), or in anaqueous solution of an inorganic acid such as hydrochloric acid andsulfuric acid. Suitably, it may be carried out in the presence of awater-miscible organic solvent, for example, methanol, or an ether suchas 1,2-dimethoxyethane, dioxane or tetrahydrofuran, at a temperature ofambient to 75° C. (preferably more than 37° C.).

And the compound (VII) may be obtained by subjecting an acid additionsalt of the compound represented by the general formula (II) and thecompounds represented by the general formula: ##STR25## (wherein allsymbols are the same meaning as described hereinbefore.) toesterification reaction.

The said reaction may be carried out by the same conditions as mentionedabove.

The compound represented by the formula (VIII) can be obtained bysubjecting the compounds represented by the general formula: ##STR26##(wherein all symbols are the same meaning as described hereinbefore.) tothe reaction for eliminating a benzyl group.

The said reaction for eliminating benzyl group may be carried out, forexample, in an atmosphere of hydrogen gas, using palladium-carbon ascatalyst in ethyl acetate, ethanol or benzene etc., at a temperature of0° C. to 40° C., preferably ambient.

The compounds represented the formula (IX) are known compounds or can beobtained by the known methods.

Further, of the compounds of the present invention represented by thegeneral formula (IB), those represented by the general formula:##STR27## [wherein R^(2c) represents

(i) a hydrogen atom,

(ii) an alkyl group of one to four carbon atoms,

(iii) an alkoxy group of one to four carbon atoms,

(iv) an alkoxymethyl group of two to five carbon atoms,

(v) a group represented by the formula: COOR³ (wherein R³ represents ahydrogen atom or an alkyl group of one to four carbon atoms.),

(vi) a group represented by the formula: CH₂ COOR³ (wherein R³ is thesame meaning as described hereinbefore.),

(vii) a halogen atom,

(viii) a trifluoromethyl group,

(ix) a group represented by the general formula: COR⁴ (wherein R⁴represents an alkyl group of from one to four carbon atoms, a phenylgroup, guanidinophenyl group, cyclopentylmethyl group orcyclohexylmethyl group.),

(x) a group represented by the formula: OCOR⁴ wherein R⁴ is the samemeaning as described hereinbefore.),

(xi) a group represented by the general formula: CH₂ OCOR⁴ (wherein R⁴is the same meaning as described hereinbefore.),

(xii) a group represented by the general formula: SO₂ R⁴ (wherein R⁴ isthe same meaning as described hereinbefore.),

(xiii) a group represented by the general formula: OSO₂ R⁴ (wherein R⁴is the same meaning as described hereinbefore.),

(xiv) a group represented by the general formula: CONR⁵ R⁶ (wherein R⁵and R⁶ represent a hydrogen atom an alkyl group of from one to fourcarbon atoms, a phenyl group, a benzyl group, a pyridyl groupindependently, or R⁵, R⁶ and a nitrogen atom, to which R⁵ and R⁶ arelinked, together represent a pyrrolidinyl group, a piperidino group ormorpholino group.),

(xv) a group represented by the general formula: OCONR⁵ R⁶ (wherein R⁵and R⁶ are the same meaning as described hereinbefore.),

(xvi) a group represented by the general formula: SO₂ NR⁵ R⁶ (wherein R⁵and R⁶ are the same meaning as described hereinbefore.),

(xvii) a group represented by the general formula: ##STR28## (wherein R⁵and R⁶ are the same meaning as described hereinbefore.),

(xviii) a group represented by the general formula: NHSO₂ R⁷ (wherein R⁷represents an alkyl group of from one to four carbon atoms or a phenylgroup.),

(xix) a hydroxy group,

(xx) a guanidino group,

(xxi) a benzyloxy group,

(xxii) a guanidinophenylthiomethyl group,

(xxiii) a morpholinosulfonylphenoxymethyl or

(xxiv) a pyridyloxymethyl group and symbol n' represents an integer ofone to five, and when symbol n' represents more than two, each of R^(2c)represents the same group or the different group.[may be prepared byreacting the compounds described by the general formula: ##STR29##(wherein R^(2c) and n' are the same meaning as described hereinbefore.)with a cyanamide described by the formula:

    H.sub.2 N--CN                                              (XI)

The above-mentioned reaction may be carried out by adding the startingmaterial (X) into water or an inert organic solvent such as methanol,ethanol, tetrahydrofuran, or into the mixed solvent of water andalcohol, adding thereto an excess amount of a compound of the formula(XI) under the existence of equimolecular or excess amount to thecompound (X), of a mineral acid such as hydrochloric acid, sulfuricacid, and then reacting for 15 minutes to two hours at a temperaturefrom ambient to the reflux temperature of the reaction mixture.

The desired compound prepared may be isolated and purified by the samemethod as hereinbefore described, and if required, converted into anacid addition salt thereof.

The starting material (X), used in above-mentioned reaction, may beeasily prepared by dissolving the corresponding p-nitrobenzoic acidphenyl ester compound in a lower alkanol such as ethanol, and thensubjecting to catalytic reduction in the presence of a hydrogenationcatalyst such as palladium on charcoal, palladium black, platinumdioxide or nickel at atmospheric temperature and pressure or by heatingand adding pressure.

The cyanamide (XI), another starting material, is a known compound.

EFFECT

Derivatives of p-guanidinobenzoic acid phenyl ester described by thegeneral formula (IA) and (IB), and acid addition salts thereof, of thepresent invention, have an inhibitory effect on elastase. Accordingly,it is useful for treatment and/or prevention of diseases induced by theabnormal enhancing of the degradation of elastin, collagen fiber and/orproteoglican, by the action of elastase, in mammals, especially in humanbeings.

Examples of such diseases are pulmonary emphysema, atherosclerosis andrheumatoid arthritis and the like.

An inhibitory effects of compounds on elastase were confirmed by thescreening system mentioned below.

INHIBITORY EFFECT ON ELASTASE (1) Method of Experiment

The test was carried out by the slight modification of the method ofBieth et al [see Biochem. Med., 75, 350 (1974)] using elastase fromhuman neutrophil.

Namely, it is a spectrophotometric method using the synthesizedsubstrate[succinyl-alanyl-prolyl-alanyl-p-nitroanilide(Suc-Ala-Pro-Ala-pNA, produced by peptide laboratory)] which hascomparatively high specificity on neutrophil elastase.

The reaction mixture consisted of 1 mM Suc-Ala-Pro-Ala-pNA (dissolvingin N-methylpyrrolidone to the concentration of 100 mM, and then adding1/100 amount of the solution to the reaction mixture.), 0.1M buffersolution of tris-hydrochloric acid (pH 8.0), 0.2M sodium chlorideaqueous solution, the sample solution of various concentrations andenzyme solution in a final volume of 1.0 ml was incubated at 37° C. for30 minutes.

The reaction was stopped by the addition of 100 μl of 50% acetic acidinto the reaction mixture, and then p-nitro anilide released wasmeasured on absorbance of 405 nm.

Inhibition percentage of the test compounds was calculated by thefollowing equation: ##EQU1##

(2) Results

The results are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________    Inhibitory Effect on Elastase                                                  ##STR30##                               (IB-c)                                                             Inhibitory Effect                                                             on Elastase                                     Example                                                                             Structural Formula of Sample                                                                          Inhibition                                                                            IC50                                    No.   (R.sup.2)n      Salt    % at 100 μM                                                                        (μM)                                 __________________________________________________________________________          hydrogen.sup.1  phosphate                                                                             54.6.sup.2                                      2     2-methyl        mesylate                                                                              20.2                                            3     3-methyl        mesylate                                                                              45.6                                                  4-methyl.sup.1  mesylate                                                                              28.4                                            4     2,3-dimethyl    mesylate                                                                              5.9                                             5     3,5-dimethyl    mesylate                                                                              46.2                                            6     3-ethyl         mesylate                                                                              39.6                                            7     2-methoxy       mesylate                                                                              23.1                                            8     3-methoxy       mesylate                                                                              50.9    100                                     9     4-methoxy       mesylate                                                                              44.4                                            10    3,5-dimethoxy   acetate         40.0                                    11    5-etanesulfonyloxy-3-                                                                         acetate 66.0    60.0                                          methoxymethyl                                                           12    3-hydroxy-5-methoxymethyl                                                                     acetate 14.0    >200                                    13    5-(4-guanidinobenzoyloxy)-                                                                    2 acetate                                                                             89.0    9.1                                           3-methoxymethyl                                                         148   3-carboxy-2-chloro                                                                            hydrobromide    20.0                                    147   3,5-dicarboxy   hydrobromide                                                                          25.0                                            149   2-carboxy-5-chloro                                                                            hydrobromide    60.0                                    14    2-chloro-3-methoxycarbonyl                                                                    mesylate                                                                              90.7    4.0                                     15    2-chloro-4-methoxycarbonyl                                                                    mesylate                                                                              55.6    98.0                                    16    3-chloro-4-methoxycarbonyl                                                                    mesylate                                                                              42.0                                            17    5-chloro-2-methoxycarbonyl                                                                    mesylate                                                                              92.2    5.8                                     18    3-chloro-5-methoxycarbonyl                                                                    acetate         1.8                                     19    3,5-bis(isopropoxycarbonyl)                                                                   mesylate                                                                              5.2                                             20    5-chloro-2-     mesylate        14.0                                          isopropoxycarbonyl                                                      21    2-chloro-3-     mesylate        2.0                                           isopropoxycarbonyl                                                      22    3-sec-butoxycarbonyl-2-                                                                       mesylate        2.6                                           chloro                                                                  23    3-methoxycarbonylmethyl                                                                       acetate 15.6                                            24    2-chloro-3-     mesylate        50.0                                          methoxycarbonylmethyl                                                                         mesylate                                                25    2-chloro-4-     mesylate                                                                              40.0                                                  methoxycarbonylmethyl                                                   26    3-chloro-4-     mesylate                                                                              13.3                                                  methoxycarbonylmethyl                                                   27    4-(2-methoxycarbonylvinyl)                                                                    mesylate                                                                              31.0                                            28    2-fluoro        mesylate                                                                              76.3    40.0                                    29    3-fluoro        mesylate                                                                              81.1    21.0                                    30    4-fluoro        mesylate                                                                              10.7                                            31    2,6-difluoro    mesylate        3.7                                     32    2,3-difluoro    acetate         3.7                                     33    2,3,4,5,6-pentafluoro                                                                         mesylate                                                                              92.1    5.8                                     34    2-chloro        mesylate                                                                              76.8    27.0                                    35    3-chloro        mesylate                                                                              87.6    8.0                                     36    4-chloro        mesylate                                                                              14.9.sup.2                                      37    2,5-dichloro    mesylate                                                                              85.8    1.1                                     38    2,6-dichloro    mesylate                                                                              89.9    2.0                                     1     3,5-dichloro    mesylate                                                                              97.0    0.4                                     39    3-chloro-5-methoxy                                                                            mesylate                                                                              91.1    2.4                                     40    4-chloro-3-methoxy                                                                            mesylate                                                                              39.0                                            41    2-chloro-5-methoxy                                                                            acetate         13.0                                    42    2-bromo         mesylate                                                                              82.1    16.0                                    43    3-bromo         mesylate                                                                              91.7    6.0                                     44    4-iodo          mesylate                                                                              11.2                                            45    2-trifluoromethyl                                                                             mesylate                                                                              72.4    23.0                                    46    3-trifluoromethyl                                                                             mesylate                                                                              71.4    13.0                                    47    3,5-bistrifluoromethyl                                                                        mesylate        3.2                                     48    3-acetyl        mesylate                                                                              4.1                                             49    2-acetyl-5-methoxy                                                                            acetate         40.0                                    50    2-acetyl-5-propoxy                                                                            mesylate        54.0                                    51    2-acetyl-5-chloro                                                                             acetate         1.8                                     52    5-chloro-2-propionyl                                                                          mesylate        1.6                                     53    5-chloro-2-isobutylyl                                                                         acetate         6.5                                     54    3-benzoyl       mesylate        92.0                                    55    4-benzoyl       mesylate                                                                              33.3                                            56    4-benzoyl-2-chloro                                                                            mesylate                                                                              57.1    48.0                                    57    4-benzoyl-2,3-dichloro                                                                        mesylate                                                                              50.5                                            58    5-chloro-2-     acetate         1.9                                           cyclopentylacetyl                                                       59    3-acetoxy       acetate 25.7                                            60    4-acetoxy       mesylate                                                                              27.8                                            61    5-acetoxy-3-chloro                                                                            acetate         0.48                                    62    3-chloro-5-propionyloxy                                                                       acetate         0.38                                    63    3-benzyloxy     mesylate                                                                              78.3    11.0                                    64    3-(4-guanidinobenzoyloxy)                                                                     acetate         15.0                                    65    3,5-bis(4-      3 mesylate                                                                            38.0                                                  guanidinobenzoyloxy)                                                    66    3-acetyl-5-(4-  2 acetate       72.0                                          guanidinobenzoyloxy)                                                    67    5-(4-guanidinobenzoyloxy)-                                                                    2 acetate       70.0                                          3-methoxycarbonyl                                                       68    3-chloro-5-(4-  acetate         0.6                                           guanidinobenzoyloxy)                                                    69    5-(4-guanidinobenzoyloxy)-                                                                    2 acetate       1.6                                           3-methoxy                                                               70    5-(4-guanidinobenzoyloxy)-                                                                    acetate         6.4                                           3-methyl                                                                71    5-acetoxymethyl-3-chloro                                                                      acetate         3.0                                     72    4-mesyl         mesylate        >100.0                                  73    5-mesyloxy-3-methoxy                                                                          acetate         4.7                                     74    3-chloro-5-mesyloxy                                                                           acetate         1.0                                     75    3-chloro-5-     acetate         1.1                                           ethanesulfonyloxy                                                       76    3-chloro-5-     acetate         1.1                                           isopropanesulfonyloxy                                                   77    5-benzenesulfonyloxy-3-                                                                       acetate         0.8                                           chloro                                                                  78    5-etanesulfonyloxy-3-methyl                                                                   acetate         27.0                                    79    5-carbamoyl-3-chloro                                                                          acetate         5.2                                     80    3-(N,N-dimethylcarbamoyl)                                                                     mesylate                                                                              30.0                                            81    2-chloro-3-(N-  mesylate        6.0                                           methylcarbamoyl)                                                        82    3-(4-guanidinobenzoyloxy)-                                                                    2 acetate                                                                             38.0                                                  5-(N-methylcarbamoyl)                                                   83    3,5-bis(N-ethylcarbamoyl)                                                                     mesylate                                                                              28.0                                            84    3,5-bis(N-propylcarbamoyl)                                                                    mesylate                                                                              36.0                                            85    5-(N-benzylcarbamoyl)-3-(4-                                                                   2 acetate                                                                             27.0                                                  guanidinobenzoyloxy)                                                    86    3-chloro-5-{N-(3-                                                                             2 acetate       0.93                                          pyridyl)carbamoyl}                                                      87    3-chloro-5-(N,N-                                                                              acetate         0.76                                          dimethylcarbamoyloxy)                                                   88    3-chloro-5-(N-ethyl-                                                                          mesylate        1.1                                           carbamoyloxy)                                                           89    3-sulfamoyl     acetate         65.0                                    90    3-chloro-4-(N,N-                                                                              acetate         140.0                                         dimethylsulfamoyl)                                                      91    2-(N,N-diethylsulfamoyl)                                                                      mesylate        180.0                                   92    3-(N,N-diethylsulfamoyl)                                                                      mesylate        35.0                                    93    4-(N,N-diethylsulfamoyl)                                                                      mesylate        58.0                                    94    3-chloro-4-(N,N-                                                                              acetate         22.0                                          diethylsulfamoyl)                                                       95    3-chloro-5-(N,N-                                                                              acetate         4.8                                           diethylsulfamoyl)                                                       96    4-(N,N-diethylsulfamoyl)-2-                                                                   acetate         61.0                                          fluoro                                                                  97    4-(N,N-dipropylsulfamoyl)                                                                     mesylate        58.0                                    98    4-(1-priolidinylsulfonyl)                                                                     acetate         77.0                                    99    3-piperidinosulfonyl                                                                          acetate 41.0                                            100   3-morpholinosulfonyl                                                                          acetate 44.2                                            101   4-morpholinosulfonyl                                                                          acetate 34.9                                            102   3-chloro-5-{N-(4-                                                                             acetate         1.3                                           sulfamoylphenyl)carbamoyl}                                              103   3-chloro-5-[N-{4-(N,N-                                                                        acetate         0.95                                          dimethylsulfamoyl)phenyl}                                                     carbamoyl                                                               104   3-chloro-5-[N-{4-(N,N-                                                                        acetate         1.1                                           diethylsulfamoyl)phenyl}                                                      carbamoyl                                                               105   2-chloro-5-(N-mesylamino)                                                                     acetate         8.5                                     106   3-chloro-5-(N-  acetate         15.0                                          ethanesulfonylamino                                                     107   3-nitro         mesylate                                                                              87.0    11.0                                    108   4-nitro         mesylate                                                                              60.1    120.0                                   109   3-hydroxy-5-methyl                                                                            acetate         160.0                                   110   5-hydroxy-3-methoxy                                                                           acetate         20.0                                    111   5-hydroxy-3-methoxycarbonyl                                                                   acetate 45.0                                            112   3-chloro-5-hydroxy                                                                            mesylate        8.3                                     113   3-(4-guanidinobenzoyloxy)-                                                                    2 mesylate                                                                            42.0                                                  5-hydroxy                                                               114   5-hydroxy-3-(N- acetate 22.0                                                  methylcarbamoyl)                                                        115   3-(N-benzylcarbamoyl)-5-                                                                      acetate         88.0                                          hydroxy                                                                 150   3-chloro-5-hydroxymethyl                                                                      acetate         4.5                                     116   3-guanidino     2 acetate                                                                             20.0                                            117   4-guanidino     2 mesylate      >100.0                                  118   2-chloro-5-guanidino                                                                          2 acetate       47.0                                    119   5-benzyloxy-3-chloro                                                                          acetate         4.7                                     120   3-chloro-5-(4-  2 acetate       6.0                                           guanidinophenylthiomethyl)                                              151   3-chloro-5-     acetate         1.4                                           morpholinosulfonyl-                                                           phenoxymethyl                                                           152   3-methoxy-5-(4- acetate         7.0                                           morpholinosulfonyl)                                                           phenoxymethyl                                                           121   3-chloro-5-(3-pyridyl)                                                                        2 acetate       1.1                                           oxymethyl                                                               122   3-methoxy-5-(3'-                                                                              acetate         12.0                                          sulfonylpyrrolidine)                                                          carboxamido                                                             123   3-chloro-5-(3'- acetate         3.1                                           sulfonypyrrolidine)                                                           carboxamido                                                             __________________________________________________________________________     Remarks:                                                                      .sup.1 shows that this compound is described in Example 4 in the              specification of Japanese Patent Kokai No. 504038.                            .sup.2 shows inhibition percentage when the concentration of drug is 50       μg/ml.                                                                

Remarks:

(1) shows that this compound is described in Example 4 in thespecification of Japanese Patent Kokai No. 50-4038.

(2) shows inhibition percentage when the concentration of drug is 50μg/ml.

    ______________________________________                                                              Elastase Inhibitory                                                           Effect                                                                              Inhibi-                                           Ex-                         tion %                                            ample Structural Formula of Sample                                                                        at       IC.sub.50                                No.   (R.sup.2)n      Salt      50 μg/ml                                                                          (μM)                                ______________________________________                                        124   hydrogen        Phosphate 94.0   2.1                                    125   2-methyl        mesylate  76.3   20                                     126   3-methyl        mesylate  89.7   5.0                                    127   4-methyl        tosylate  29.3                                          128   2-methoxy       mesylate  79.8   21.0                                   129   3-methoxy       sulfonate 89.2   6.4                                    130   4-methoxy       mesylate  48.2                                          131   4-fluoro        mesylate  83.0   21.0                                   132   2-chloro        mesylate  93.0   1.8                                    133   3-chloro        mesylate  81.2   0.3                                    134   4-chloro        mesylate  69.5                                          135   2,5-dichloro    mesylate  92.1   0.1                                    136   2,6-dichloro    mesylate  64.5   45                                     137   3,4-dichloro    mesylate  35.5                                          138   2-bromo         mesylate  83.1   1.6                                    139   4-carboxyl      mesylate  23.2                                          140   4-carboxymethyl sulfonate 47.8                                          141   2-methoxycarbonyl                                                                             mesylate  96.3   2.6                                    142   4-ethoxycarbonyl                                                                              mesylate  69.1                                          144   4-ethoxycarboxymethyl                                                                         mesylate  75.5                                          145   4-nitro         mesylate  64.2   18.0                                   146   4-(N,N-         acetate   73.1   11.0                                         acethylaminosulfonyl)                                                   ______________________________________                                    

The result of the experiment showed that the compounds of the presentinvention have an inhibitory effect on elastase.

Further, it was confirmed that the toxicity of the compounds of thepresent invention is enough low and they can be useful enough safely formedical supplies.

For example, in the acute toxicity test in mice by intravenousadministration, the LD₅₀ values of compounds wherein Y represents anoxygen atom in the general formula (IB) and (R²)n represents2,5-dichloro, a hydrogen atom, 3-chloro-5-hydroxy,3-chloro-5-ethanesulfonyloxy and 3-chloro-4-(N,N-diethylsulfamoyl), werebetween 50 and 150 mg/kg, respectively.

The other the LD₅₀ values of compounds wherein Y represents a sulfuratom in the general formula (IB) and (R²)n represents 2,5-dichlorogroup, a hydrogen atom, 3-chloro-5-hydroxy, 3-chloro-5-ethanesulfonyloxyand 3-chloro-4-(N,N-diethylsulfamoyl), were between 50 and 150 mg/kg,respectively.

Accordingly, it was confirmed that the compounds of the presentinvention can be useful for the treatment and/or prevention of diseasesinduced by abnormal enhancing of degradation of proteins such as elastinand the like, by the action of elastase in mammals, especially in humanbeings.

For the purpose mentioned above, the compounds of the present invention,described in the general formula (IA) and (IB) or an acid addition saltsthereof may normally be administered systemically or partially, usuallyby oral or parenteral administration.

The dose to be administered is determined depending upon age, bodyweight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person for one time are generally between 50 mg and500 mg, by oral administration up to several times per day, and between10 mg and 200 mg, by parenteral administration (preferably byintravenous administration) up to several times per day.

As mentioned above, the doses to be used depend on various conditions.Therefore, there are cases in which doses lower than the rangesspecified above and doses greater than the ranges specified above, maybe used.

Solid compositions according to the present invention for oraladministration include compressed tablets, dispersible powders andgranules. In such solid compositions, one or more of the activecompound(s) is, or are, admixed with at least one inert diluent such aslactose, mannitol, glucose, hydroxypropyl cellulose, microcrystallinecellulose, starch, polyvinylpyrrolidone or magnesium metasilicatealuminate. The compositions may also comprise, as is normal practice,additional substances other than inert diluents e.g. lubricating agentssuch as magnesium stearate, and, disintegrating agents such as cellulosecalcium gluconate, stabilizing agents such as lactose, and solubilizerssuch as glutamic acid and asparaginic acid. The tablets or pills may, ifdesired, be made into gastric film-coated or enteric film-coated tabletsor pills, such as sugar-coated, gelatin-coated,hydroxypropylcellulose-coated or hydroxypropylmethylcellulosephthalate-coated tablets or pills; two or more layers may be used. Thecompositions for oral administration also include capsules of absorbablematerial such as gelatin.

Liquid compositions for oral administration includepharmaceutically-acceptable emulsions, solutions, suspensions, syrupsand elixirs containing inert diluents commonly used in the art such asdistilled water or ethanol. Besides inert diluents such compositions mayalso comprise adjuvants such as wetting and suspending agents, andsweetening, flavouring, perfuming and preserving agents.

Other compositions for oral administration include spray compositionswhich may be prepared by known methods and which comprise one or more ofthe active compound(s). Besides inert diluents such compositions mayalso comprise stabilizers such as sodium bisulfite and buffer forisotonicity, for example sodium chloride, sodium citrate or citric acid.

The manufacturing methods of spray compositions have been described indetail, for example, specifications of the U.S. Pat. Nos. 2,868,691 and3,095,355.

Preparations for injection according to the present invention forparenteral administration include sterile aqueous or non-aqueoussolutions, suspensions or emulsions. Example of aqueous solvents orsuspending media are distilled water for injection and physiologicalsalt solution. Examples of non-aqueous solvents or suspending media arepropylene glycol, polyethylene glycol, vegetable oils such as olive oil,alcohols such as ethanol, Polysorbate 80 (registered Trade Mark). Thesecompositions may also include adjuvants such as preserving, wetting,emulsifying and dispersing agents stabilizing agents (e.g. lactose) andsolubilizers (e.g. glutamic acid and asparaginic acid). They may besterilized, for example, by filtration through a bacteria-retainingfilter, by incorporation of sterilizing agents in the compositions or byirradiation. They may also be manufactured in the form of sterile solidcompositions which can be dissolved in sterile water or some othersterile injectable medium immediately before use.

Other compositions for parenteral administration include liquids forexternal use, and endermic liniments such as ointments, suppositoriesfor rectal administration and pessaries for vaginal administration whichcomprise one or more of the active compound(s) and may be prepared byknown methods.

EXAMPLE

The following Reference Examples and Examples illustrate the preparationof compounds of the present invention, however, the present invention isnot restricted to them. In the Examples, "IR" represents "Infraredabsorption spectrum". Except when specified otherwise, infraredabsorption spectra were recorded by KBr tablet. In the table, "Mesylate"represents "methansulfonyl group".

EXAMPLE 1 p-guanidinobenzoic acid 3,5-dichlorophenyl estermethanesulfonate ##STR31##

The mixture of 700 mg of p-guanidinobenzoyl chloride hydrochloride(prepared by the methods described in Example 1 of each of thespecification of Japanese Patent Kokai No. 55-115865 and U.S. Pat. No.4,283,418), 490 mg of 3,5-dichlorophenol and 10 ml of pyridine wasstirred for thirty minutes. Diethyl ether was added into the reactionmixture, and the mixture was decanted.

A saturated aqueous solution of sodium bicarbonate was added into theobtained layer of ether to obtain the desired carbonate.

The obtained crystal was washed with water and acetone, successive, wasdried in vacuum.

Dried crystal was suspended in ethanol, 0.124 ml of methanesulfonic acidwas added thereto, and precipitated crystal was dried in vacuum to give506 mg of the title compound (white crystal) having the followingphysical data: melting point: 232°-234° C.; IR value: υ 3340, 3150,1730, 1680, 1620, 1600, 1570, 1550, 1410, 1260, 1200, 1170, 1090, 1060,1040 cm⁻¹.

Hereinafter, by the same procedure as described in Example 1,p-guanidinobenzoyl chloride hydrochloride and desired phenol compound orthiophenol compounds were used to obtain compounds of the presentinvention described in following table 2 [compound (IB) wherein Y is anoxygen atom] and table 3 [compounds (IB) wherein Y is a sulfur atom].##STR32##

                                      TABLE 2                                     __________________________________________________________________________    Example                                                                            The Structure of Products                                                                            The Appearance                                    No.  (R.sup.2)n       HX (Salt)                                                                           of Products                                                                              m.p. and IR Value of                   __________________________________________________________________________                                           Products                                    hydrogen         phosphate                                                                           white crystal                                                                            205˜208° C.                2   2-methyl         mesylate                                                                            yellow crystal                                                                           199˜200° C.                3   3-methyl         mesylate                                                                            white powder                                                                             143˜144° C.                4   2,3-dimethyl     mesylate                                                                            yellow crystal                                                                           202˜205° C.                5   3,5-dimethyl     mesylate                                                                            pale yellow crystal                                                                      184˜185° C.                6   3-ethyl          mesylate                                                                            white crystal                                                                            142˜143° C.                7   2-methoxy        mesylate                                                                            white crystal                                                                            196˜197° C.                8   3-methoxy        mesylate                                                                            white crystal                                                                            162˜164° C.                9   4-methoxy        mesylate                                                                            pink crystal                                                                             173˜174° C.               10   3,5-dimethoxy    acetate                                                                             yellow wax ν 2900˜3400, 1730,                                                   1570˜1610, 1470,                                                        1420, 1260, 1130, 1070,                                                       1040 cm.sup.-1 (neat)                  11   5-etanesulfonyloxy-3-                                                                          acetate                                                                             pale brown bubbly                                                                        ν 2500˜3500, 1730, 1680,                                             1570,                                       methoxymethyl          powder     1400, 1360, 1255, 1170, 1110,                                                 1070 cm.sup.-1                         12   3-hydroxy-5-methoxymethyl                                                                      acetate                                                                             creamy colored                                                                           ν 3700˜3300, 3300˜                                             2300, 1720, 1685,                                                  bubbly powder                                                                            1600, 1570, 1450, 1410, 1265,                                                 1135, 1080 cm.sup.-1                   13   5-(4-guanidinobenzoyloxy)-3-                                                                   2 acetate                                                                           brown bubbly powder                                                                      ν 3700˜2250, 1740, 1690,                                             1560,                                       methoxymethyl                     1400, 1260, 1180, 1125,                                                       1070 cm.sup.-1                         14   2-chloro-3-methoxycarbonyl                                                                     mesylate                                                                            white powder                                                                             188˜190° C.               15   2-chloro-4-methoxycarbonyl                                                                     mesylate                                                                            white powder                                                                             206˜207° C.               16   3-chloro-4-methoxycarbonyl                                                                     mesylate                                                                            pink powder                                                                              206˜210° C.               17   5-chloro-2-methoxycarbonyl                                                                     mesylate                                                                            white powder                                                                             170˜175° C.               18   3-chloro-5-methoxycarbonyl                                                                     acetate                                                                             white bubbly powder                                                                      ν 3480, 3000, 1730, 1600,                                                  1640,                                                                         1580, 1420, 1260, 1170, 1100,                                                 1060 cm.sup.-1                         19   3,5-bis(isopropoxycarbonyl)                                                                    mesylate                                                                            white crystal                                                                            155˜157° C.               20   5-chloro-2-isopropoxycarbonyl                                                                  mesylate                                                                            white crystal                                                                            202˜203°0 C.              21   2-chloro-3-isopropoxycarbonyl                                                                  mesylate                                                                            white bubbly powder                                                                      ν 3300, 3150, 1720, 1680,                                                  1600,                                                                         1570, 1240, 1040 cm.sup.-1             22   3-sec-butoxycarbonyl-2-chloro                                                                  mesylate                                                                            white crystal                                                                            177˜180° C.               23   3-methoxycarbonylmethyl                                                                        acetate                                                                             colorless oil                                                                            ν 3500˜3300,                                                         1700˜1500, 1400 cm.sup.-1                                               (neat)                                 24   2-chloro-3-methoxycarbonylmethyl                                                               mesylate                                                                            white crystal                                                                            194˜196° C.               25   2-chloro-4-methoxycarbonylmethyl                                                               mesylate                                                                            white powder                                                                             170˜171° C.               26   3-chloro-4-methoxycarbonylmethyl                                                               mesylate                                                                            white powder                                                                             181˜182° C.               27   4-(2-methoxycarbonylvinyl)                                                                     mesylate                                                                            pink crystal                                                                             225˜230° C.               28   2-fluoro         mesylate                                                                            pink crystal                                                                             168˜170° C.               29   3-fluoro         mesylate                                                                            white crystal                                                                            97˜101° C.                30   4-fluoro         mesylate                                                                            white crystal                                                                            163˜164° C.               31   2,6-difluoro     mesylate                                                                            white powder                                                                             219˜221° C.               32   2,3-difluoro     acetate                                                                             white crystal                                                                            >300° C.                        33   2,3,4,5,6-pentafluoro                                                                          mesylate                                                                            white crystal                                                                            181˜183° C.               34   2-chloro         mesylate                                                                            pale orange crystal                                                                      198˜200° C.               35   3-chloro         mesylate                                                                            white crystal                                                                            200˜202° C.               36   4-chloro         mesylate                                                                            white crystal                                                                            185˜188° C.               37   2,5-dichloro     mesylate                                                                            white crystal                                                                            221˜223° C.               38   2,6-dichloro     mesylate                                                                            pink crystal                                                                             234˜237° C.               39   3-chloro-5-methoxy                                                                             mesylate                                                                            white powder                                                                             205˜207° C.               40   4-chloro-3-methoxy                                                                             mesylate                                                                            white powder                                                                             125˜128° C.               41   2-chloro-5-methoxy                                                                             acetate                                                                             white bubbly powder                                                                      ν 3360, 3000, 1745, 1680,                                                  1600,                                                                         1570, 1500, 1410, 1260, 1160,                                                 1080, 1020 cm.sup.-1                   42   2-bromo          mesylate                                                                            pale pink crystal                                                                        194˜197° C.               43   3-bromo          mesylate                                                                            white crystal                                                                            212˜214° C.               44   4-iodo           mesylate                                                                            white crystal                                                                            174˜176°  C.              45   2-trifluoromethyl                                                                              mesylate                                                                            white crystal                                                                            191˜193° C.               46   3-trifluoromethyl                                                                              mesylate                                                                            white crystal                                                                            195˜198° C.               47   3,5-bistrifluoromethyl                                                                         mesylate                                                                            yellow powder                                                                            194˜198° C.               48   3-acetyl         mesylate                                                                            white crystal                                                                            180˜182° C.               49   2-acetyl-5-methoxy                                                                             acetate                                                                             brown wax  ν 2900˜3500, 1730, 1680,                                             1480,                                                                         1260, 1140 cm.sup.-1 (neat)            50   2-acetyl-5-propoxy                                                                             mesylate                                                                            brown oil  ν 3300, 3150, 1740, 1670,                                                  1600,                                                                         1560, 1060, 1040 cm.sup.-1 (neat)      51   2-acetyl-5-chloro                                                                              acetate                                                                             brown bubbly powder                                                                      ν 3400, 3000, 1740, 1690,                                                  1600,                                                                         1570, 1400, 1260, 1180,                                                       1060 cm.sup.-1                         52   5-chloro-2-propionyl                                                                           mesylate                                                                            white bubbly powder                                                                      ν 3400, 3000, 1740, 1690,                                                  1590,                                                                         1440, 1410, 1370, 1250, 1180,                                                 1120, 1070 cm.sup.-1                   53   5-chloro-2-isobutyryl                                                                          acetate                                                                             yellow bubbly                                                                            ν 3350, 3000, 1735, 1680,                                                  1580,                                                              powder     1400, 1260, 1200, 1170, 1080,                                                 1060, 1010 cm.sup.-1                   54   3-benzoyl        mesylate                                                                            white powder                                                                             172˜175° C.               55   4-benzoyl        mesylate                                                                            brown powder                                                                             218˜220° C.               56   4-benzoyl-2-chloro                                                                             mesylate                                                                            white powder                                                                             190˜192°  C.              57   4-benzoyl-2,3-dichloro                                                                         mesylate                                                                            white powder                                                                             169˜173° C.               58   5-chloro-2-cyclopentylacetyl                                                                   acetate                                                                             white bubbly powder                                                                      ν 3350, 2950, 1540, 1690,                                                  1600,                                                                         1570, 1400, 1260, 1200, 1180,                                                 1060 cm.sup.-1                         59   3-acetoxy        acetate                                                                             brown wax  ν 3350, 3150, 1720, 1680,                                                  1610,                                                                         1580, 1410, 1270, 1140, 1080,                                                 1050 cm.sup.-1 (neat)                  60   4-acetoxy        mesylate                                                                            pale brown wax                                                                           ν 3650˜2500, 1760, 1740,                                             1700,                                                                         1680, 1630, 1610, 1570, 1510,                                                 1470, 1410, 1375, 1280 cm.sup.-1       61   5-acetoxy-3-chloro                                                                             acetate                                                                             white bubbly powder                                                                      ν 3400, 3100, 1740, 1685,                                                  1600,                                                                         1400, 1320, 1260, 1140, 1070,                                                 1010 cm.sup.-1                         62   3-chloro-5-propionyloxy                                                                        acetate                                                                             pale brown ν 2500˜3500, 1720, 1680,                                             1580,                                                              amorphous  1400 cm.sup.-1                         63   3-benzoyloxy     mesylate                                                                            pale brown wax                                                                           ν 3200, 1730, 1680, 1600,                                                  1570,                                                                         1480, 1450, 1410, 1250,                                                       1130 cm.sup.-1 (neat)                  64   3-(4-guanidinobenzoyloxy)                                                                      acetate                                                                             white bubbly powder                                                                      ν 3350, 3150, 1730, 1680,                                                  1600,                                                                         1570, 1250, 1170, 1130, 1060,                                                 1040, 1020 cm.sup.-1                   65   3,5-bis(4-guanidinobenzoyloxy)                                                                 3 mesylate                                                                          pale yellow bubbly                                                                       ν 3350, 3150, 1730, 1680,                                                  1600,                                                              powder     1560, 1450, 1250, 1170, 1120,                                                 1060, 1040 cm.sup.-1                   66   3-acetyl-5-(4-   2 acetate                                                                           while solid                                                                              ν 3650˜2200, 1740, 1690,                                             1570,                                       guanidinobenzoyloxy)              1410, 1260, 1180, 1135,                                                       1070 cm.sup.-1                         67   5-(4-guanidinobenzoyloxy)-3-                                                                   2 acetate                                                                           pale brown solid                                                                         ν 3650˜2300, 1730, 1690,                                             1570,                                       methoxycarbonyl                   1400, 1260 cm.sup.-1                   68   3-chloro-5-(4-   acetate                                                                             yellow bubbly                                                                            ν 3150, 1740, 1680, 1600,                                                  1560,                                       guanidinobenzoyloxy)   powder     1440, 1270, 1180, 1130, 1060,                                                 1040 cm.sup.-1                         69   5-(4-guanidinobenzoyloxy)-3-                                                                   2 acetate                                                                           colorless solid                                                                          ν 3650˜2200, 1740, 1690,                                             1610,                                       methoxy                           1570, 1410, 1260, 1180, 1150,                                                 1130, 1070, 1020 cm.sup.-1             70   5-(4-guanidinobenzoyloxy)-3-                                                                   2 acetate                                                                           pale brown bubbly                                                                        ν 2500˜3600, 1720, 1680,                                             1560,                                       methyl                 powder     1400, 1260, 1175, 1120,                                                       1070 cm.sup.-1                         71   5-acetoxymethyl-3-chloro                                                                       acetate                                                                             colorless oil                                                                            ν 3400, 1730, 1680, 1560,                                                  1400,                                                                         1240, 1170, 1140, 1060, 1010,                                                 860, 740, 640 cm.sup.-1                72   4-mesyl          mesylate                                                                            white powder                                                                             200˜215° C.               73   5-mesyloxy-3-methoxy                                                                           acetate                                                                             white bubbly powder                                                                      ν 3400, 1730, 1680, 1600,                                                  1400,                                                                         1360, 1260, 1180, 1140, 1110,                                                 1060 cm.sup.-1                         74   3-chloro-5-mesyloxy                                                                            acetate                                                                             white bubbly powder                                                                      ν 3400, 3000, 1740, 1690,                                                  1600,                                                                         1440, 1410, 1370, 1250, 1180,                                                 1120, 1070 cm.sup.-1                   75   3-chloro-5-ethanesulfonyloxy                                                                   acetate                                                                             white bubbly powder                                                                      ν 3350, 3000, 1740, 1680,                                                  1590,                                                                         1560, 1400, 1260, 1200, 1180,                                                 1060, 1020 cm.sup.-1                   76   3-chloro-5-isopropanesulfonyloxy                                                               acetate                                                                             white bubbly powder                                                                      ν 3400, 2900, 1740, 1640,                                                  1600,                                                                         1430, 1400, 1240, 1180, 1110,                                                 1060 cm.sup.-1                         77   5-benzenesulfonyloxy-3-chloro                                                                  acetate                                                                             white bubbly powder                                                                      190˜195° C.               78   5-etanesulfonyloxy-3-methyl                                                                    acetate                                                                             pale brown bubbly                                                                        ν 2500˜3600, 1730, 1680,                                             1560,                                                              powder     1400, 1260, 1170, 1110 cm.sup.-1       79   5-carbamoyl-3-chloro                                                                           acetate                                                                             white amorphous                                                                          ν 3400, 1680, 1570, 1400,                                                  1300,                                                                         1270, 1230, 1180, 1100, 1080,                                                 1010, 880, 850, 760, 650                                                      cm.sup.-1                              80   3-(N,N-dimethyl)carbamoyl                                                                      mesylate                                                                            white solid                                                                              ν 3650˜3200, 3150, 1735,                                             1680,                                                              (hygroscopicity)                                                                         1600, 1570, 1510, 1480, 1450,                                                 1400, 1310, 1280, 1200,                                                       1060 cm.sup.-1                         81   2-chloro-3-(N-methylcarbamoyl)                                                                 mesylate                                                                            white crystal                                                                            201˜205° C.               82   3-(4-guanidinobenzoyloxy)-5-(N-                                                                2 acetate                                                                           colorless solid                                                                          ν 3650˜2300, 1740, 1690,                                             1560,                                       methylcarbamoyl)                  1510, 1400, 1250, 1180, 1125,                                                 1065 cm.sup.-1                         83   3,5-bis(N-ethylcarbamoyl)                                                                      mesylate                                                                            brown wax  ν 3200, 1735, 1680, 1640,                                                  1560,                                                                         1260, 1200, 1050 cm.sup.-1             84   3,5-bis(N-propylcarbamoyl)                                                                     mesylate                                                                            yellow bubbly                                                                            ν 3300, 3150, 1730, 1640,                                                  1560,                                                              powder     1260, 1200, 1040 cm.sup.-1             85   5-(N-benzylcarbamoyl)-3-(4-                                                                    2 acetate                                                                           colorless solid                                                                          ν 3650˜2300, 1740, 1700,                                             1640,                                       guanidinobenzoyloxy)              1600, 1570, 1420, 1260, 1190,                                                 1140, 1080 cm.sup.-1                   86   3-chloro-5-{N-(3-                                                                              2 acetate                                                                           pale brown bubbly                                                                        ν 3400, 3100, 1740, 1680,                                                  1580,                                       pyridyl)carbamoyl}     powder     1480, 1420, 1410, 1260,                                                       1080 cm.sup.-1                         87   3-chloro-5-(N,N- acetate                                                                             white bubbly powder                                                                      ν 3400, 3000, 1730, 1700,                                                  1580,                                       dimethylcarbamoyloxy)             1440, 1390, 1260, 1160, 1130,                                                 1070 cm.sup.-1                         88   3-chloro-5-(N-ethylcarbamoyloxy)                                                               mesylate                                                                            white bubbly powder                                                                      ν 3400, 3150, 1730, 1680,                                                  1600,                                                                         1570, 1440, 1260, 1200, 1140,                                                 1060 cm.sup.-1                         89   3-sulfamoyl      acetate                                                                             white crystal                                                                            ν 3430, 1735, 1690, 1570,                                                  1410,                                                                         1270, 1210, 1180, 1160, 1075,                                                 1010, 765 cm.sup.-1                    90   3-chloro-4-(N,N- acetate                                                                             yellow bubbly                                                                            ν 3400, 3000, 1740, 1690,                                                  1570,                                       dimethylsulfamoyl)     powder     1410, 1340, 1250, 1200, 1160,                                                 1060 cm.sup.-1                         91   2-(N,N-diethylsulfamoyl)                                                                       mesylate                                                                            white powder                                                                             ν 3350, 3130, 2980, 1740,                                                  1675,                                                                         1600, 1565, 1470, 1330, 1260,                                                 1200, 1055, 1015, 940, 785, 760,                                              715 cm.sup.-1                          92   3-(N,N-diethylsulfamoyl)                                                                       mesylate                                                                            white powder                                                                             ν 3350, 3150, 2980, 1735,                                                  1680,                                                                         1600, 1565, 1465, 1330, 1260,                                                 1200, 1065, 1040, 1015, 935,                                                  780, 760, 715 cm.sup.-1                93   4-(N,N-diethylsulfamoyl)                                                                       mesylate                                                                            white crystal                                                                            ν 3400, 3130, 1735, 1695,                                                  1565,                                                                         1325, 1270, 1205, 1175, 1150,                                                 1075, 1040, 1015, 945, 720                                                    cm.sup.-1                              94   3-chloro-4-(N,N- acetate                                                                             pale brown bubbly                                                                        ν 3400, 2500, 1740, 1680,                                                  1560,                                       diethylsulfamoyl)      powder     1400, 1250, 1200, 1140, 1060,                                                 1010 cm.sup.-1                         95   3-chloro-5-(N,N- acetate                                                                             pale brown wax                                                                           ν 3650˜2100, 1050, 1010,                                             935, 805,                                   diethylsulfamoyl)                 755 cm.sup.-1 (neat)                   96   4-(N,N-diethylsulfamoyl)-2-                                                                    acetate                                                                             yellow wax ν 3400, 3000, 1740, 1680,                                                  1560,                                       fluoro                            1500, 1410, 1260, 1140, 1070,                                                 1050, 1010 cm.sup.-1                   97   4-(N,N-dipropyl)sulfamoyl                                                                      mesylate                                                                            white crystal                                                                            ν 3400, 2980, 1735, 1675,                                                  1600,                                                                         1575, 1350, 1265, 1205, 1160,                                                 1050 cm.sup.-1                         98   4-(1-pyrrolidinylsulfonyl)                                                                     acetate                                                                             pale brown solid                                                                         ν 3700˜2200, 1740, 1690,                                             1590,                                                                         1510, 1405, 1340, 1265, 1205,                                                 1160, 1100, 1065, 1015 cm.sup.-1       99   3-piperidinosulfonyl                                                                           acetate                                                                             white solid                                                                              ν 3650˜3000, 2940, 2850,                                             1740,                                                                         1680, 1570, 1405, 1340, 1265,                                                 1205, 1170, 1070 cm.sup.-1             100  3-morpholinosulfonyl                                                                           acetate                                                                             white solid                                                                              ν 3650˜3000, 2960, 2850,                                             1740,                                                                         1680, 1570, 1405, 1355, 1270,                                                 1210, 1170, 1115, 1070 cm.sup.-1       101  4-morpholinosulfonyl                                                                           acetate                                                                             pale yellow solid                                                                        ν 3700˜2300, 1740, 1710,                                             1690,                                                                         1570, 1400, 1350, 1270, 1210,                                                 1160, 1120, 1100, 1060,                                                       1020 cm.sup.-1                         102  3-chloro-5-{N-(4-                                                                              acetate                                                                             pale brown ν 2500˜3500, 1720(S),                                                1660, 1560,                                 sulfamoylphenyl)carbamoyl}                                                                           amorphous  1520, 1400 cm.sup.-1                   103  3-chloro-5-[N-{4-(N,N-                                                                         acetate                                                                             white bubbly powder                                                                      ν 3400, 1730, 1670, 1570,                                                  1510,                                       dimethylsulfamoyl)phenyl}         1400, 1320, 1250, 1170, 1150,               carbamoyl]                        1060, 1010, 950, 880, 840, 760,                                               720, 710 cm.sup.-1                     104  3-chloro-5-[N-{4-(N,N-                                                                         acetate                                                                             while bubbly powder                                                                      ν 3400, 1735, 1680, 1580,                                                  1400,                                       diethylsulfamoyl)phenyl}          1320, 1260, 1150, 1070,                     carbamoyl]                        1020 cm.sup.-1                         105  2-chloro-5-(N-mesylamino)                                                                      acetate                                                                             white crystal                                                                            ν 3450, 3100, 2860˜2200,                                             1750,                                                                         1695, 1570, 1480, 1405, 1335,                                                 1245, 1175, 1145, 1065,                                                       1050 cm.sup.-1 (neat)                  106  3-chloro-5-(N-   acetate                                                                             pale yellow bubbly                                                                       ν 3400, 3150, 1770, 1740,                                                  1680,                                       ethanesulfonylamino)   powder     1590, 1400, 1260, 1200, 1130,                                                 1070 cm.sup.-1                         107  3-nitro          mesylate                                                                            white crystal                                                                            162˜166° C.               108  4-nitro          mesylate                                                                            pale brown crystal                                                                       228˜231° C.               109  3-hydroxy-5-methyl                                                                             acetate                                                                             yellow bubbly                                                                            ν 2500˜3500, 1720, 1680,                                             1400,                                                              powder     1320, 1260, 1170, 1120 cm.sup.-1       110  5-hydroxy-3-methoxy                                                                            acetate                                                                             colorless solid                                                                          ν 3650˜2200, 1730, 1690,                                             1600,                                                                         1570, 1410, 1270, 1160,                                                       1130 cm.sup.-1                         111  5-hydroxy-3-methoxycarbonyl                                                                    acetate                                                                             pale yellow solid                                                                        ν 3650˜2300, 1720, 1695,                                             1600,                                                                         1570, 1440, 1410, 1330, 1260,                                                 1145 cm.sup.-1                         112  3-chloro-5-hydroxy                                                                             mesylate                                                                            pale brown powder                                                                        170˜173° C.               113  3-(4-guanidinobenzoyloxy)-5-                                                                   2 mesylate                                                                          brown bubbly powder                                                                      ν 3350, 3150, 1730, 1680,                                                  1600,                                       hydroxy                           1570, 1460, 1400, 1260, 1180,                                                 1120, 1040 cm.sup.-1                   114  5-hydroxy-3-(N-methylcarbamoyl)                                                                acetate                                                                             pale yellow solid                                                                        ν 3650˜2300, 1720, 1610,                                             1570,                                                                         1410, 1270, 1150 cm.sup.-1             115  3-(N-benzylcarbamoyl)-5-hydroxy                                                                acetate                                                                             colorless solid                                                                          ν 3650˜2300, 1740, 1700,                                             1650,                                                                         1600, 1520, 1410, 1340, 1260,                                                 1150, 1080 cm.sup.-1                   116  3-guanidino      2 acetate                                                                           pale brown bubbly                                                                        ν 3000˜3500, 1720, 1680,                                             1560,                                                              powder     1390, 1250, 1160, 1060,                                                       1010 cm.sup.-1                         117  4-guanidino      2 mesylate                                                                          brown bubbly powder                                                                      ν 3400, 3150, 1730, 1670,                                                  1620,                                                                         1600, 1570, 1510, 1260, 1200,                                                 1040 cm.sup.-1                         118  2-chloro-5-guanidino                                                                           2 acetate                                                                           white solid                                                                              ν 3700˜2300, 1740, 1690,                                             1560,                                                                         1400, 1260, 1180, 1070,                                                       1015 cm.sup.-1                         119  5-benzyloxy-3-chloro                                                                           acetate                                                                             pale brown ν 3400, 1580, 1415, 1265,                                       amorphous  1140 cm.sup.-1                         120  3-chloro-5-(4-   2 acetate                                                                           pale brown ν 3350, 1725, 1670, 1560,                                                  1400,                                       guanidinophenylthiomethyl)                                                                           amorphous  1250, 1180, 1140, 1070,                                                       1010 cm.sup.-1                         121  3-chloro-5-(3-pyridyl)oxymethyl                                                                2 acetate                                                                           white bubbly powder                                                                      ν 3400, 1740, 1710, 1580,                                                  1410,                                                                         1270, 1260, 1180 cm.sup.-1             122  3-methoxy-5-(1,1-dioxothiazol-3-                                                               acetate                                                                             pale gray bubbly                                                                         ν 3600˜2500, 1720, 1660,                                             1640,                                       yl)carbonyl            powder     1560, 1400, 1310, 1250 cm.sup.-1       123  3-chloro-5-(1,1-dioxothiazol-3-                                                                acetate                                                                             white bubbly powder                                                                      ν 3600˜2700, 1730, 1640,                                             1570,                                       yl)carbonyl                       1400, 1320, 1260, 1240                 __________________________________________________________________________                                           cm.sup.-1                               ##STR33##

                                      TABLE 3                                     __________________________________________________________________________    Example                                                                            The Structure of Products                                                                         The Appearance                                       No.  (R.sup.2)n    HX (Salt)                                                                           of Products                                                                             m.p. and IR Value of                       __________________________________________________________________________                                       Products                                   124  hydrogen      phosphate                                                                           white crystal                                                                           207˜210° C.                   125  2-methyl      mesylate                                                                            pale yellow powder                                                                      197˜198° C.                   126  3-methyl      mesylate                                                                            white powder                                                                            203˜205° C.                   127  4-methyl      p-tosylate                                                                          white crystal                                                                           238˜240° C.                   128  2-methoxy     mesylate                                                                            white crystal                                                                           184˜186° C.                   129  3-methoxy     mesylate                                                                            white powder                                                                            188˜190° C.                   130  4-methoxy     mesylate                                                                            pale yellow powder                                                                      164˜165° C.                   131  4-fluoro      mesylate                                                                            pale yellow crystal                                                                     238˜241° C.                   132  2-chloro      mesylate                                                                            white powder                                                                            183˜184° C.                   133  3-chloro      mesylate                                                                            white crystal                                                                           185˜190° C.                   134  4-chloro      mesylate                                                                            white crystal                                                                           213.8˜216° C.                 135  2,5-dichloro  mesylate                                                                            white powder                                                                            209˜210° C.                   136  2,6-dichloro  mesylate                                                                            white powder                                                                            190˜195° C.                   137  3,4-dichloro  mesylate                                                                            white powder                                                                            217˜219° C.                   138  2-bromo       mesylate                                                                            white powder                                                                            190˜193° C.                   139  4-carboxy     mesylate                                                                            white crystal                                                                           232˜233° C.                   140  4-carboxymethyl                                                                             sulfonate                                                                           white crystal                                                                           228˜232° C.                   141  2-methoxycarbonyl                                                                           mesylate                                                                            white powder                                                                            167˜169° C.                   142  4-ethoxycarbonyl                                                                            phosphate                                                                           white crystal                                                                           188˜190° C.                   143  4-ethoxycarbonyl                                                                            mesylate                                                                            white crystal                                                                           205˜206° C.                   144  4-ethoxycarbonylmethyl                                                                      mesylate                                                                            white crystal                                                                           60˜65° C.                     145  4-nitro       mesylate                                                                            pale yellow powder                                                                      212˜215° C.                   146  4-(N,N-diethylaminosulfonyl)                                                                mesylate                                                                            gray bubbly powder                                                                      ν 3400, 3000, 1675, 1560, 1400,                                            1330, 1260, 1200, 1170, 1150,                                                 1010 cm.sup.-1                             __________________________________________________________________________

EXAMPLE 147 P-guanidinobenzoic acid 3-carboxy-2-chlorophenylesterhydrobromide ##STR34##

4 ml of 1N sodium hydroxide was added into 700 mg of3-carboxy-2-chlorophenol, and the mixture was concentrated under reducedpressure to obtain corresponded sodium salt. The sodium salt wasdissolved in 20 ml of hexamethylphospholamide, and 0.58 ml ofbenzylbromide was added into the mixture. The mixture was stirred forone night.

The reaction mixture was diluted with diethylether, and was washed withwater and a saturated aqueous solution of sodium chloride. And themixture was dried over absolute sodium sulfate, and was concentratedunder reduced pressure.

The residue and one g of p-guanidinobenzoyl chloride hydrochloride(prepared by the methods described in Example 1 of each of thespecification of Japanese Patent Kokai No. 55-115865 and U.S. Pat. No.4,283,418) was stirred for fifteen minutes in pyridine in ice-waterbath.

Diethylether was added into the reaction mixture, :ne reaction mixturewas decantated, a saturated aqueous solution cf sodium bicarbonate wasadded into insoluble residue and the crystal was filtered off. Further,the crystal was washed with successive, water and acetone, and dried invacuum.

About 5 ml of 30% hydrogen bromide-acetic acid was added into 200 mg ofthe obtained crystal in an atmosphere of argon, and the mixture wasstirred for three hours at ambient temperature. Diethylether was addedinto the reaction mixture, the precipitated crystal was washed withdiethylether, dried in vacuum to give 192 mg of the title compound(yellow powder) having the following physical data:

melting point: 220°˜227° C.

Hereinafter, by the same procedure as described in Example 147, thecompounds of the present invention, Example 148 and Example 149, havingthe following physical data described in Table 4 were obtained.

                                      TABLE 4                                     __________________________________________________________________________    Example                                                                            The Structure of Products                                                                      The Appearance                                          No.  (R.sup.2)n                                                                              HX (Salt)                                                                            of Products                                                                            m.p. and IR Value of Products                  __________________________________________________________________________    148  3,5-dicarboxy                                                                           hydrobromide                                                                         yellow powder                                                                          210˜214° C.                       149  2-carboxy-5-chloro                                                                      hydrobromide                                                                         yellow crystal                                                                         bubbly at more than 150° C.                                            (gradually decomposed)                         __________________________________________________________________________

EXAMPLE 150 P-guanidinobenzoic acid 3-chloro-5-hydroxymethylphenylesteracetate ##STR35##

1.970 g of 3-chloro-5-hydroxydbenzoic acid was dissolved in 30 ml ofdimethylformamide. 601 mg of sodium hydride was added to the mixture andstirred for ten minutes at ambient temperature.

4.288 g of benzyl bromide was added into the reaction mixture, stirredfor two hours at ambient temperature. 30 ml of ethyl acetate was addedinto the reaction mixture, further the reaction mixture was washed withwater at several times. The mixture was dried with absolute magnesiumsulfate, and concentrated under reduced pressure. The obtained residuewas purified by column chromatography on silica-gel (elusion solvent,hexane:ethyl acetate=10:1) to give 3.61 g of 3-chloro-5-benzyloxybenzoicacid benzylester having the following physical data; TLC (hexane:ethylacetate=10:1): Rf 0.26.

3.61 g of the benzyl compound was dissolved in 50 ml of tetrahydrofuran.579 mg of lithiumaluminiumhydride was added into the mixture, reactedfor two hours at ambient temperature.

Ethyl acetate was added into the reaction mixture to analyse the excessreagent. The mixture was poured into 1N sodium hydroxide. The reactionmixture was extracted with diethylether, and the extract was dried overabsolute magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica-gel (elusionsolvent, dichloromethane) to give 1.502 g of3-chloro-5-benzyloxybenzylalcohol having the following physical data;TLC (chloroform:methanol=10:1): Rf 0.69.

1.502 g of the alcohol compound was dissolved in 20 ml ofdichloromethane. 655 mg of 2,3-dihydropyran and catalytic amount ofp-toluenesulfonic acid were added thereto, and the mixture was reactedfor one hour at ambient temperature.

A little amount of pyridine was added into the reaction mixture, and themixture was washed with water, and concentrated under reduced pressure.

The obtained residue was purified by column chromatography on silica-gel(elusion solvent, hexane:ethyl acetate=10:1) to give 1.83 g of3-chloro-5-benzyloxybenzylalcohol-O-(2-tetrahydropyranyl)ether havingthe following physical data; TLC (hexane:ethyl acetate=10:1): Rf 0.20.

996 mg of obtained the benzyl compound was dissolved in 7 ml of ethylacetate, this solution was reacted for eliminating benzyl group using10% palladium carbon as catalyst at the atmospheric temperature andpressure and under an atmosphere of hydrogen. After three hours, thereaction was stopped, the obtained crude product was purified by columnchromatography on silica-gel (elusion solvent, hexane:ethyl acetate=5:1)to give 274 mg of 3-chloro-5-(2-tetrahydropyranyloxymethyl)phenol havingthe following physical data; TLC (hexane:ethyl acetate=5:3): Rf 0.24.

274 mg of the phenol compound was dissolved in 3 ml of pyridine, 396 mgof p-guanidinobenzoyl chloride hydrochloride was added into the mixtureand reacted for two hours at ambient temperature.

20 ml of diethylether was added into the reaction mixture, theprecipitate was filtered off. And further, the precipitate was washedwith diethylether. An aqueous solution of sodium bicarbonate was addedinto the insoluble residue, and the produced carbonate was filtered off.

The crude carbonate was dissolved in 3 ml of 60% acetic acid, reactedfor two hours at 37° C.

Acetic acid was distilled off under reduced pressure, the residue waspurified oy column chromatography on silica-gel (elusion solvent,chloroform:methanol:acetic acid=10:2:1) to give 100 mg of the titlecompound having the following physical data; TLC(chloroform:methanol:acetic acid=10:2:1): Rf 0.26 NMR (CD₃ OD): δ 8.2(2H, d, J=8 Hz), 7.42 (2H, d, J=5 Hz), 7.30 (1H, bs), 7.16 (2H, bs),4.64 (2H, s).

EXAMPLE 151 P-guanidinobenzoic acid3-chloro-5-(4-morpholinosulfonyl)phenoxymethylphenylester acetate##STR36##

4.04 mg of 3-chloro-5-hydroxybenzoic acid was dissolved in 10 ml ofdichloromethane, and 256 mg of 2,3-dihydropyran was added into themixture. The catalytic amount of p-toluenesulfonic acid was addedthereto, and the mixture was reacted for one hour at ambienttemperature.

A little amount of pyridine was added into the reaction mixture, and theobtained mixture was washed with water, dried over absolute magnesiumsulfate, and concentrated under reduced pressure to give thecorresponded (2-tetrahydropyranyl) ether.

The obtained crude product was used in the next reaction withoutpurifying.

That is, the crude product was dissolved in 10 ml of tetrahydrofuran,and cooled in the ice-water bath. 133 mg of lithiumaluminiumhydride wasadded thereto, and the mixture was stirred. The reaction temperature wasrised to ambient temperature, and the mixture was further reacted forone hour. Ethyl acetate was added into the reaction mixture to analysethe excess reagent.

The reaction mixture was poured into 20 ml of 1N sodium hydroxide. Themixture was extracted with ethyl acetate, and the extract wasconcentrated under reduced pressure. The residue was purified by columnchromatography or silica-gel (elusion solvent, hexane:ethyl acetate=5:2)to give 541 mg of 3-chloro-5-(2-tetrahydropyranyloxy)benzylalcoholhaving the following physical data; TLC (hexane:ethyl acetate=5:3): Rf0.5.

484 mg of the alcohol thus obtained was dissolved in 10 ml ofdichloromethane. 242 mg of triethylamine was added thereto and themixture was cooled in ice-water bath. Further 273 mg ofmethanesulfonylchloride was added dropwise to the mixture. After thereaction temperature was rised to ambient temperature, the mixture waswashed with water, dried over absolute magnesium sulfate, andconcentrated under reduced pressure to give the corresponded mesylate.

The obtained crude product was used to the next reaction withoutpurifying.

460 mg of p-morpholinosulfonylphenol was dissolved into the mixture of 7ml of tetrahydrofuran and 1 ml of hexamethylphosphoramide. 57.6 mg ofsodium hydride was added thereto, and the mixture was stirred for tenminutes.

Secondly, mesylate obtained above was added into this reaction solution,reacted for one hour at ambient temperature.

Water was added into the reaction mixture, and the mixture was extractedwith ethyl acetate. The extract was washed with water, dried overabsolute magnesium sulfate, and concentrated under reduced pressure.

The obtained crude product was dissolved in the mixture solvent of 5 mlof methanol and 5 ml of tetrahydrofuran. Further, 50 mg ofp-toluenesulfonic acid was added into the mixture, reacted for two hoursat ambient temperature to distill off the solvent. The residue waspurified by column chromatography on silica-gel (hexane:ethylacetate=5:3) to give 228 mg of3-chloro-5-(4-morphosulfonyl)phenoxymethylphenol having the followingphysical data; TLC (hexane:ethyl acetate=5:3): Rf 0.18.

By using 228 mg of the phenol compound thus obtained, 207 mg ofp-guanidinobenzoyl chloride hydrochloride and 3 ml of pyridine, theesterification was carried out by the same procedure as described inExample 1.

The product was purified by column chromatography on silica-gel (elusionsolvent, ether acetate:acetic acid:water=400:100:30) to give 150 mg oftitle compound having the following physical data; TLC(chloroform:methanol:acetic acid=10:2.1): Rf 0.7; IR: ν 3600-2500, 1720,1680, 1560, 1400, 1330 cm⁻¹.

EXAMPLE 152 p-guanidinobenzoic acid3-methoxy-5-(4-morpholinosulfonyl)phenoxymethylphenylester acetate##STR37##

By the same procedure as described in Example 151, the title compound(white powder) having the following physical data was obtained.

TLC (ethyl acetate:acetic acid:water=400:100:30): Rf 0.72; IR: ν2500˜3600, 1720, 1680, 1590, 1400, 1340 cm⁻¹.

PREPARATIVE EXAMPLE 1

10 g of p-guanidinobenzoic acid 3-chloro-5-hydroxyphenyl estermethanesulfonate (prepared in Example 112), 400 mg of cellulose calciumgluconate (disintegrator), 200 mg of magnesium stearate (lubricator) and9.4 g of microcrystalline cellulose were admixed and punched out inconventional manner to give 100 tablets each containing 100 mg of theactive ingredient.

PREPARATIVE EXAMPLE 2

One g of p-guanidinobenzoic acid 3-chloro-5-hydroxyphenyl estermethanesulfonate (prepared in Example 112) was dissolved in 10 ml ofethanol and the solution was sterilized by filtration through abacteria-retaining filter, and placed 0.5 ml portions into 5 ml ampoulesto obtain ampoules each containing 50 mg of the active ingredient, andthe ampoules were then sealed. The contents of ampoules are used forinjection by diluting with a trishydrochloric acid buffer solution (pH8.6) to 2.5 ml.

PREPARATIVE EXAMPLE 3

10 g of p-guanidinobenzoic acid 3-chloro-5-ethanesulfonyloxyphenyl esteracetate (prepared in Example 75), 400 mg of cellulose calcium gluconate(disintegrator), 200 mg of magnesium stearate (lubricator) and 9.4 g ofmicrocrystalline cellulose were admixed and punched out in conventionalmanner to give 100 tablets each containing 100 mg of the activeingredient.

PREPARATIVE EXAMPLE 4

One g of p guanidinobenzoic acid 3-chloro-5-ethanesulfonyloxyphenylester acetate (prepared in Example 75), was dissolved in 10 ml ofethanol and the solution was sterilized by filtration through abacteria-retaining filter, and placed 0.5 ml portions into 5 ml ampoulesto obtain ampoules each containing 50 mg of the active ingredient, andthe ampoules were then sealed. The contents of ampoules are used forinjection by diluting with a tris-hydrochloric acid buffer solution (pH8.6) to 2.5 ml.

PREPARATIVE EXAMPLE 5

10 g of p-guanidinobenzoic acid 2,5-dichlorothiophenyl estermethanesulfonate (prepared in Example 135), 400 mg of cellulose calciumgluconate (disintegrator), 200 mg of magnesium stearate (lubricator) and9.4 g of microcrystalline cellulose were admixed and punched out inconventional manner to give 100 tablets each containing 100 mg of theactive ingredient.

PREPARATIVE EXAMPLE 6

One g of p-guanidinobenzoic acid 2,5-dichlorothiophenyl estermethanesulfonate (prepared in Example 135) was dissolved in 10 ml ofethanol and the solution was sterilized by filtration through abacteria-retaining filter, and placed 0.5 ml portions into 5 ml ampoulesto obtain ampoules each containing 50 mg of the active ingredient, andthe ampoules were then sealed. The contents of ampoules are used forinjection by diluting with a suitable quantity of dilution, for example,by diluting with a trishydrochloric acid buffer solution (pH 8.6) to 2.5ml.

What we claim is:
 1. A method for the treatment and/or prevention ofdiseases induced by abnormal enhancing of degradation of proteins by theaction of elastase in mammals subject to or suffering therefrom, whichcomprises administering an effective amount of derivatives ofp-guanidinobenzoic acid of the general formula: ##STR38## where Yrepresents an oxygen atom R represents a halogen atom, and R²represents(i) a hydrogen atom, (ii) an alkyl group of one to four carbonatoms, (iii) an alkoxy group of one to four carbon atoms, (iv) analkoxymethyl group of two to five carbon atoms, (v) a group representedby the formula: COOR³, wherein R³ represents a hydrogen atom or an alkylgroup of one to four carbon atoms, (vi) a group represented by theformula: CH₂ COOR³, wherein R³ has the same meaning as describedhereinbefore, (vii) a group represented by the formula: CH═CH--COOR³,wherein R³ has the same meaning as described hereinbefore, (viii) ahalogen atom, (ix) a trifluoromethyl group (x) a group represented bythe formula: COR⁴, wherein R⁴ represents an alkyl group of one to fourcarbon atoms, a phenyl group, a guanidinophenyl group, acyclopentylmethyl group or a cyclohexylmethyl group, (xi) a grouprepresented by the formula: OCOR⁴, wherein R⁴ has the same meaning asdescribed hereinbefore, (xii) a group represented by the formula: CH₂OCOR⁴, wherein R⁴ has the same meaning as described hereinbefore, (xiii)a group represented by the formula: SO₂ R⁴, wherein R⁴ has the samemeaning as described hereinbefore, (xiv) a group represented by theformula: OSO₂ R⁴, wherein R⁴ has the same meaning as describedhereinbefore, (xv) a group represented by the formula: CONR⁵ R⁶, whereinR⁵ and R⁶ represent a hydrogen atom, an alkyl group of from one to fourcarbon atoms, a phenyl group, a benzyl group, a pyridyl groupindependently, or R⁵, R⁶ and a nitrogen atom, to which R⁵ and R⁶ arelinked, together represent a pyrrolidinyl group, a piperidino group or amorpholino group, (xvi) a group represented by the formula: OCONR⁵ R⁶,wherein R⁵ and R⁶ have the same meaning as described hereinbefore,(xvii) a group represented by the formula: SO₂ NR⁵ R⁶, wherein R⁵ and R⁶have the same meaning as described hereinbefore; (xviii) a grouprepresented by the formula: ##STR39## wherein R⁵ and R⁶ have the samemeaning as described hereinbefore, (xix) a group represented by theformula: NHSO₂ R⁷, wherein R⁷ represents an alkyl group or from one tofour carbon atoms or a phenyl group, (xx) a nitro group, (xxi) a hydroxygroup, (xxii) a hydroxymethyl group, (xxiii) a guanidino group, (xxiv) abenzyloxy group, (xxv) a guanidinophenylthiomethyl group, (xxvi) amorpholinosulfonylphenoxymethyl group, (xxvii) a pyridyloxymethyl group,or (xxviii) a (1,1-dioxothiazol-3-yl)carbonyl group,and n" represents aninteger of one to four, and (1) when n" represents two or more, each ofR² may be the same group or a different group, and (2) when R representsa 3-chloro atom, R² does not represent 5-OSO₂ R⁴, wherein R⁴ has thesame meaning as described hereinbefore, or a non-toxic acid additionsalt thereof.
 2. A method according to claim 1 in which the activeingredient is p-guanidinobenzoic acid 3-chloro-5-hydroxyphenyl ester.